title: Discovery of 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. Part 1: Structure-activity relationships of the 1- and 3-positions.
abstract: 1-Benzoyl-3-cyanopyrrolo[1,2-a]quinoline (2a) was identified as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 2a had good activity against several breast cancer cell lines but was much less active against several other cancer cell lines. SAR studies of 2a found that substitution at the 4-position of the 1-benzoyl group was important for activity. Replacing the 3-cyano group by an ester or ketone group led to inactive compounds. Interestingly, 4-substituted analogs such as 1-(4-(1H-imidazol-1-yl)benzoyl)-3-cyanopyrrolo[1,2-a]quinoline (2k) were found to be broadly and highly active in the caspase activation assay as well as in the cell growth inhibition assay with low nM EC(50) and GI(50) values in human breast cancer cells T47D, human colon cancer cells HCT116, and hepatocellular carcinoma cancer cells SNU398. Compound 2a was found not to inhibit tubulin polymerization up to 50 microM, while 2k was found to inhibit tubulin polymerization with an IC(50) value of 5 microM, indicating that certain substituents at the 4-position of the 1-benzoyl group can change the mechanism of action.
authors.affiliation: Epicept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kemnitzer
authors.forename: Jared
authors.initials: J
authors.lastname: Kuemmerle
authors.forename: Songchun
authors.initials: S
authors.lastname: Jiang
authors.forename: Han-Zhong
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Nilantha
authors.initials: N
authors.lastname: Sirisoma
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Candace
authors.initials: C
authors.lastname: Crogan-Grundy
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C534174:1-benzoyl-3-cyanopyrrolo(1,2-a)quinoline; D000970:Antineoplastic Agents; D011804:Quinolines; D050257:Tubulin Modulators; D020169:Caspases